Publications by authors named "Huabing Yang"

20 Publications

  • Page 1 of 1

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation.

Int J Radiat Oncol Biol Phys 2021 May 8. Epub 2021 May 8.

Department of Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.

Methods And Materials: The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array.

Results: Patients with R/D lesions receiving CSI (n = 32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P = .0493), IL-6 (P = .0111), and IL-10 (P = .0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P < .0001, P = .018, P < .0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively.

Conclusions: CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.041DOI Listing
May 2021

Chitosan oligosaccharides attenuate loperamide-induced constipation through regulation of gut microbiota in mice.

Carbohydr Polym 2021 Feb 13;253:117218. Epub 2020 Oct 13.

College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, PR China; Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, PR China.

This study was designed to explore the improvement of chitosan oligosaccharides (COS) on constipation through regulation of gut microbiota. Here, we proved that COS treatment profoundly boosted intestinal motility, restrained inflammatory responses, improved water-electrolyte metabolism and prevented gut barrier damage in constipated mice induced by loperamide. By 16S rDNA gene sequencing, the disbalanced gut microbiota was observed in constipated mice, while COS treatment statistically reversed the abundance changes of several intestinal bacteria at either phylum, family and genus levels, which partly led to the balance in production of intestinal metabolites including bile acids, short-chain fatty acids and tryptophan catabolites. In addition, COS failed to relieve the constipation in mice with intestinal flora depletion, confirming the essentiality of gut microbiota in COS-initiated prevention against constipation. In summary, COS can ameliorate the development of loperamide-induced constipation in mice by remodeling the structure of gut microbial community.
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http://dx.doi.org/10.1016/j.carbpol.2020.117218DOI Listing
February 2021

Bile acid profiles in bile and feces of obese mice by a high-performance liquid chromatography-tandem mass spectrometry.

Biotechnol Appl Biochem 2020 Nov 2. Epub 2020 Nov 2.

College of Life Sciences, Wuchang University of Technology, Wuhan, People's Republic of China.

Bile acids (BAs) play a pivotal role in manipulating the development of metabolic diseases. However, due to the compositional complexity and functional variation of BAs, it remains unclear about the changes in BA pool for individuals with obesity or metabolic syndrome. We established a high-performance liquid chromatography-mass spectrometer detection system for the simultaneous analysis of both unconjugated and conjugated BAs in the bile and feces of mice. Ten BAs were completely separated, identified, and quantified with low limit of detection (0.5 ng/mL) and inter/intraday precision (relative standard deviation < 12%). By using this method, these BAs in bile and feces of mice were quantified. The result showed that taurochenodeoxycholic acid, taurine-conjugated α-muricholic acids, and taurine-conjugated β-muricholic acids were the dominated BAs in bile, whereas deoxycholic acid and chenodeoxycholic acid predominated in feces. Further, most of the BA levels were significantly elevated in either bile or fecal samples of high-fat diet-fed mice as compared with those in normal chow diet-fed mice, indicating that excessive production of BAs was closely associated with the occurrence of lipid metabolism disorders. In summary, the present method is practicable for analysis of BAs in bile and fecal samples of patients with obesity.
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http://dx.doi.org/10.1002/bab.2055DOI Listing
November 2020

Integrative analysis of hepatic metabolomic and transcriptomic data reveals potential mechanism of nonalcoholic steatohepatitis in high-fat diet-fed mice.

J Diabetes 2020 Oct 6. Epub 2020 Oct 6.

College of Life Sciences, Wuchang University of Technology, Wuhan, China.

Background: Due to the complex pathogenesis, the molecular mechanism of nonalcoholic steatohepatitis (NASH) remains unclear. In this study, we aimed to reveal the comprehensive metabolic and signaling pathways in the occurrence of NASH.

Methods: C57BL/6 mice were treated with high-fat diet for 4 months to mimic the NASH phenotype. After the treatment, the physiochemical parameters were evaluated, and the liver tissues were prepared for untargeted metabolomic analysis with ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, three relevant Gene Expression Omnibus (GEO) datasets were selected for integrative analysis of differentiated messenger RNA and metabolites.

Results: The levels of phosphatidylethanolamine (PE) (16:1(9Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, and sphingomyelin (SM) (d18:0/12:0) were significantly increased, and the content of adenosine was severely reduced in NASH mice. The integrated interpretation of transcriptomic and metabolomic data indicated that the glycerophospholipid metabolism and necroptosis signaling were evidently affected in the development of NASH. The high level of SM (d18:0/12:0) may be related to the expression of acid sphingomyelinase (ASMase), and the elevated arachidonic acid was coordinated with the upregulation of cytosol phospholipase A2 (cPLA2) in the necroptosis pathway.

Conclusions: In summary, the inflammatory response, necroptosis, and glycerophospholipid may serve as potential targets for mechanistic exploration and clinical practice in the treatment of NASH.
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http://dx.doi.org/10.1111/1753-0407.13120DOI Listing
October 2020

Quantitative analysis of total methenolone in animal source food by liquid chromatography-tandem mass spectrometry.

Drug Test Anal 2021 Jan 6;13(1):148-155. Epub 2020 Sep 6.

School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China.

Methenolone, an anabolic androgenic steroid, has been applied to improve the quality and protein content of meat in animal husbandry. However, the usage of methenolone in sports is banned for its doping effects. Several methods have been reported to monitor the content of methenolone in serum and urine samples, but a highly sensitive detection system has not been developed for the determination of methenolone in animal source food due to its constituent complexity. In this study, a novel detection system was developed to quantify the contents of both free and conjugated methenolone in animal source food including pork, beef, mutton, milk, and eggs by using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) coupled with delicate pretreatment procedures. The conjugated methenolone in the above food samples was released by dual enzyme digestion, and the total methenolone was extracted by 1% formic acid in acetonitrile, followed by the purification using a PRiME HLB column or QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) salt. The compound d -methyltestosterone was used as an internal standard to minimize matrix interference. Finally, a wide linear range (0.5-20 μg/kg), low limit of detection (LOD) (0.3 μg/kg), good precision (<7% relative standard deviation), and high recovery (>90%) were obtained in the study of method validation. In summary, this analytical method provides a practicable monitoring tool for the quantification of methenolone in animal source food.
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http://dx.doi.org/10.1002/dta.2915DOI Listing
January 2021

Effect of Chitosan oligosaccharides on ischemic symptom and gut microbiota disbalance in mice with hindlimb ischemia.

Carbohydr Polym 2020 Jul 25;240:116271. Epub 2020 Apr 25.

College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China; Chongqing Academy of Chinese Materia Medica, Nanshan Road 34, Chongqing 400065, PR China. Electronic address:

This study was designed to explore the effect of Chitosan oligosaccharides (COS) on mouse hindlimb ischemia by femoral artery ligation. Here, we demonstrated that COS treatment statistically promoted the blood perfusion and neovascularization in ischemic hindlimb of mice, accompanied by the suppression of inflammation and oxidative stress. By 16S rDNA gene sequencing, the disbalanced gut microbiota was observed in ischemic mice, while COS treatment, at least in part, restored the abundance changes of some intestinal bacteria at either phylum or genus levels. Based on metabolomics analysis on mouse plasma by UPLC-QTOF-MS, we screened 20 metabolites with the largest responses to ischemia, several of which were markedly reversed by COS. By Spearman's correlation analysis, the changed metabolites might act as a bridge between improved intestinal bacterial structure and alleviated hindlimb ischemia of mice treated by COS. Our studies point towards a potential role of COS in treatment of peripheral ischemia diseases.
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http://dx.doi.org/10.1016/j.carbpol.2020.116271DOI Listing
July 2020

Ginsenoside Rb1 retards aging process by regulating cell cycle, apoptotic pathway and metabolism of aging mice.

J Ethnopharmacol 2020 Jun 9;255:112746. Epub 2020 Mar 9.

Hubei University of Chinese Medicine, Wuhan, Hubei, 430065, China. Electronic address:

Ethnopharmacological Relevance: Ginsenoside Rb1 (GRb1), an active ingredient of traditional Chinese medicine Panax ginseng C. A. Meyer, has displayed various activities such as antioxidative stress, autophagic regulation and apoptotic inhibition. However, the role of GRb1 in natural aging process remains unclear.

Aim Of The Study: In this study, we investigated the anti-aging effect and underlying molecular mechanisms of ginsenoside Rb1 in natural aging process.

Materials And Methods: We treated the natural aging C57BL/6J mice by intragastrical administration of GRb1 (100 mg/kg·BW) every other day for 10 months and investigated the effect of GRb1 on aging symptoms. By RT-qPCR and WB analysis, we examined the expression levels of senescence-associated biomarkers and aging-related pathways, including cell cycle, apoptosis and inflammation in aging process. Further, metabolomics analysis was conducted to investigate the changes of aging-related metabolites after GRb1 treatment.

Results: Treatment with GRb1 significantly attenuated the aging-induced physiological changes, including slowed reduction of body weight, suppression of hair loss, decrease of arterial wall thickness and heart weight. We found that GRb1 treatment remarkably reversed the changed expression of p53-p21-Cdk2 axis in heart tissues of aging mice, which was responsible for the cell cycle repression. And the activations of apoptosis-associated factors (Bax and Caspase-3) were also inhibited by GRb1 treatment. Further, based on the serum metabolomics analysis using HPLC-MS/MS analysis, several metabolites were identified as potential biomarkers related to the anti-aging effect of GRb1, including glycerophospholipids, carboxylic acids and fatty acyls. Especially, the change of glycerophospholipid metabolism pathway was found to be the mostly changed.

Conclusion: Our studies suggest that GRb1 retards the aging process in mice by regulating cell cycle and apoptotic pathway, which were associated with the alleviation of metabolic disorders.
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http://dx.doi.org/10.1016/j.jep.2020.112746DOI Listing
June 2020

BuZangTongLuo decoction improved hindlimb ischemia by activating angiogenesis and regulating gut microbiota in diabetic mice.

J Ethnopharmacol 2020 Feb 22;248:112330. Epub 2019 Oct 22.

School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China; College of Life Sciences, Wuchang University of Technology, Wuhan, 430223, China. Electronic address:

Ethnopharmacological Relevance: Seven traditional medicinal plants (including Astragalus membranaceus, Dioscorea hemsleyi, Salvia miltiorrhiza, Scrophularia ningpoensis, Ophiopogon japonicus, Panax ginseng and Fritillariae cirrhosae) and one insect leech (Whitmania pigra Whitman) were combined into BuZangTongLuo formula (BZTLF) under the guidance of traditional Chinese medicine. BZTLF is potentially effective against diabetic vascular complications.

Aim Of The Study: Previous studies failed to clarify the molecular mechanism through which BZTLF suppressed diabetic ischemia. In this study, we aimed to explore whether BZTLF treatment could prevent the occurrence of type 2 diabetic (T2D) hindlimb ischemia in mice. Further, we investigated the regulatory effect of BZTLF on angiogenesis-related VEGF signaling pathway and gut microbiota dysfunction in diabetic ischemia mice.

Materials And Methods: C57BL/6J mice fed with high-fat diet (HFD) received STZ injection and femoral artery ligation to build T2D diabetic hindlimb ischemia model. Mice were gavaged with BZTLF (5 g [raw materials]/kg/d) or with metformin plus atorvastatin for three weeks. Laser doppler imaging system was utilized for the visualization of blood flow. Histochemistry analysis was performed for microvascular vessel staining. Western blot was applied to detect the protein changes of signaling molecules responsible for VEGF pathway. Finally, 16S rDNA gene sequencing was conducted for analysis of gut microbiota structure.

Results: BZTLF treatment remarkably restored blood flow and capillary density of diabetic hindlimb ischemia. And the protein changes of VEGF signaling molecules were reversed in BZTLF-treated diabetic ischemia mice, including the decreased VEGF and HIF-1α, and the increased NO, eNOS and p-ERK1/2. The gut microbiota analysis suggests that BZTLF treatment increased the abundances of several beneficial bacteria (Akkermansia, Bifidobacterium and Bacteroides), while decreased the populations of some harmful bacteria(Blautia, Weissella, Escherichia Shigella and Kurthia). By using Spearman's correlation analysis, these changed gut flora were positively/negatively correlated with VEGF signaling pathway or glycometabolic parameters.

Conclusion: BZTLF displayed beneficial effects on diabetic hindlimb ischemia by reshaping the gut microbiota structure and stunning the VEGF/HIF-1α pathway.
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http://dx.doi.org/10.1016/j.jep.2019.112330DOI Listing
February 2020

1-Deoxynojirimycin improves high fat diet-induced nonalcoholic steatohepatitis by restoring gut dysbiosis.

J Nutr Biochem 2019 09 8;71:16-26. Epub 2019 Jun 8.

College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei, China. Electronic address:

Non-alcoholic steatohepatitis (NASH) is associated with chronic inflammation and gut bacterial dysbiosis. Studies show that 1-deoxynojirimycin (DNJ) may improve NASH, yet the role of gut microbiota in protective effect of DNJ on NASH remains to be known. In present study, we aimed to examine how DNJ ameliorated high-fat diet (HFD)-induced mouse NASH through the regulation of gut microbiota dysbiosis. C57BL/6 J mice fed with HFD were treated with DNJ (0.1 mg/mL, in drinking water) for 4 months. The results by using histochemical staining and qPCR confirmed that DNJ remarkably modulated glucose intolerance and hyperlipidemia, attenuated hepatic steatosis and systemic chronic inflammation in HFD-induced mice. Moreover, DNJ greatly reshaped the structure of disbalanced intestinal flora, as indicated by the enhanced bacterial richness and diversity, the decreased Firmicutes-to-Bacteroidetess ratio and the increased Akkermansia level. The prediction algorithm suggests that DNJ may extensively dampen the bacterial motility and bacterial energy metabolism. Consistently, the altered gut microbiota was closely correlated with metabolic biomarkers of mice with NASH. Based on our studies, DNJ could alleviate the progress of HFD-induced NASH by rebuilding the gut microbial community structure, suggesting that DNJ may serve as a functional food to prevent or treat NASH clinically.
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http://dx.doi.org/10.1016/j.jnutbio.2019.05.013DOI Listing
September 2019

Neutralization mechanism of human monoclonal antibodies against Rift Valley fever virus.

Nat Microbiol 2019 07 1;4(7):1231-1241. Epub 2019 Apr 1.

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen that causes substantial morbidity and mortality in livestock and humans. To date, there are no licensed human vaccines or therapeutics available. Here, we report the isolation of monoclonal antibodies from a convalescent patient, targeting the RVFV envelope proteins Gn and Gc. The Gn-specific monoclonal antibodies exhibited much higher neutralizing activities in vitro and protection efficacies in mice against RVFV infection, compared to the Gc-specific monoclonal antibodies. The Gn monoclonal antibodies were found to interfere with soluble Gn binding to cells and prevent infection by blocking the attachment of virions to host cells. Structural analysis of Gn complexed with four Gn-specific monoclonal antibodies resulted in the definition of three antigenic patches (A, B and C) on Gn domain I. Both patches A and B are major neutralizing epitopes. Our results highlight the potential of antibody-based therapeutics and provide a structure-based rationale for designing vaccines against RVFV.
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http://dx.doi.org/10.1038/s41564-019-0411-zDOI Listing
July 2019

Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus.

Sci Transl Med 2016 12;8(369):369ra179

Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.

The 2015-2016 outbreak of Zika virus (ZIKV) disease has affected many countries and is a major public health concern. ZIKV is associated with fetal microcephaly and neurological complications, and countermeasures are needed to treat and prevent ZIKV infection. We report the isolation of 13 specific human monoclonal antibodies from a single patient infected with ZIKV. Two of the isolated antibodies (Z23 and Z3L1) demonstrated potent ZIKV-specific neutralization in vitro without binding or neutralizing activity against strains 1 to 4 of dengue virus, the closest relative to ZIKV. These two antibodies provided postexposure protection to mice in vivo. Structural studies revealed that Z23 and Z3L1 bound to tertiary epitopes in envelope protein domain I, II, or III, indicating potential targets for ZIKV-specific therapy. Our results suggest the potential of antibody-based therapeutics and provide a structure-based rationale for the design of future ZIKV-specific vaccines.
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http://dx.doi.org/10.1126/scitranslmed.aai8336DOI Listing
December 2016

Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway.

J Diabetes Res 2016 28;2016:9128050. Epub 2015 Dec 28.

Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.

Clopidogrel (INN), an oral antiplatelet drug, has been revealed to have a number of biological properties, for instance, anti-inflammation and antioxidation. Oxidative stress plays an imperative role in inflammation, diabetes mellitus, atherosclerosis, and cancer. In the present study, human aortic endothelial cells (HAECs) were employed to explore the anti-inflammatory activity of INN. INN reduced TNFα-induced reactive oxygen species (ROS) generation and time-dependently prompted the expression and activity of heme oxygenase 1 (HO-1). Cellular glutathione (GSH) levels were augmented by INN. shHO-1 blocked the INN suppression of TNFα-induced HL-60 cell adhesion. The CaMKKβ/AMPK pathway and Nrf2 transcriptional factor were implicated in the induction of HO-1 by INN. Additionally, TNFα dramatically augmented VCAM-1 expression at protein and mRNA levels. INN treatment strikingly repressed TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Compound C, an AMPK inhibitor, and shNrf2 abolished TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Our data suggest that INN diminishes TNFα-stimulated VCAM-1 expression at least in part via HO-1 induction, which is CaMKKβ/AMPK pathway-dependent.
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http://dx.doi.org/10.1155/2016/9128050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707324PMC
October 2016

The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa.

Sci Rep 2015 Nov 25;5:16775. Epub 2015 Nov 25.

Department of Surgery, Duke University Medical Center, 203 Research Drive, Suite 433, Box 2606, Durham, NC 27710, United States.

This study investigated interactive effects of CYP2B6 genotypes and liver metastasis on the prognosis of metastatic breast cancer patients who received combined chemotherapy of docetaxel and thiotepa. Totally 153 patients were retrospectively genotyped rs8192719 (c.1294 + 53C > T) and rs2279343 (c.785A > G). Kaplan-Meier method and Cox Proportional Hazard Regression model were used to estimate the survival. Patients with liver metastasis had worsen prognosis, conferring a 2.26-fold high risk of progression and 1.93-fold high risk of death (p < 0.05). Both CT/TT genotype of rs8192719 (c.1294 +  3C > T) and AG genotype of rs2279343 (c.785A > G) prolonged survival (p < 0.05). Furthermore, among liver metastatic patients, AG genotype of rs2279343 (c.785A > G) was associated with a 47% reduced risk of death and a 6-month-longer overall survival (p < 0.05). Among non-liver metastatic patients, hazard ratios of CT/TT genotype of rs8192719 (c.1294 + 53C > T) were 0.45 for progression and 0.40 for death; and the corresponding survival was improved by 6 months and 16 months, respectively (p < 0.05). Genotypes of CYP2B6 had an interaction with clinical efficacy of docetaxel and thiotepa on metastatic breast cancer patients; and metastatic sites also affected clinical responses. Further therapies should take into account of chemotherapy regimen, genotypes of metabolizing enzymes and metastatic sites for the particular subpopulation.
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http://dx.doi.org/10.1038/srep16775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658481PMC
November 2015

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

Int J Clin Pharmacol Ther 2015 Nov;53(11):914-22

Background: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities.

Methods: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded.

Results: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity.

Conclusions: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.
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http://dx.doi.org/10.5414/CP202391DOI Listing
November 2015

Upregulation of Unc-51-like kinase 1 by nitric oxide stabilizes SIRT1, independent of autophagy.

PLoS One 2014 26;9(12):e116165. Epub 2014 Dec 26.

Department of Medicine and Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.

SIRT1 is central to the lifespan and vascular health, but undergoes degradation that contributes to several medical conditions, including diabetes. How SIRT1 turnover is regulated remains unclear. However, emerging evidence suggests that endothelial nitric oxide synthase (eNOS) positively regulates SIRT1 protein expression. We recently identified NO as an endogenous inhibitor of 26S proteasome functionality with a cellular reporter system. Here we extended this finding to a novel pathway that regulates SIRT1 protein breakdown. In cycloheximide (CHX)-treated endothelial cells, NONOate, an NO donor, and A23187, an eNOS activator, significantly stabilized SIRT1 protein. Similarly, NO enhanced SIRT1 protein, but not mRNA expression, in CHX-free cells. NO also stabilized an autophagy-related protein unc-51 like kinase (ULK1), but did not restore SIRT1 protein levels in ULK1-siRNA-treated cells or in mouse embryonic fibroblasts (MEF) from Ulk1-/- mice. This suggests that ULK1 mediated the NO regulation of SIRT1. Furthermore, adenoviral overexpression of ULK1 increased SIRT1 protein expression, while ULK1 siRNA treatment decreased it. Rapamycin-induced autophagy did not mimic these effects, suggesting that the effects of ULK1 were autophagy-independent. Treatment with MG132, a proteasome inhibitor, or siRNA of β-TrCP1, an E3 ligase, prevented SIRT1 reduction induced by ULK1-siRNA. Mechanistically, ULK1 negatively regulated 26S proteasome functionality, which was at least partly mediated by O-linked-GlcNAc transferase (OGT), probably by increased O-GlcNAc modification of proteasomal subunit Rpt2. The NO-ULK1-SIRT1 axis was likely operative in the whole animal: both ULK1 and SIRT1 protein levels were significantly reduced in tissue homogenates in eNOS-knockout mice (lung) and in db/db mice where eNOS is downregulated (lung and heart). Taken together, the results show that NO stabilizes SIRT1 by regulating 26S proteasome functionality through ULK1 and OGT, but not autophagy, in endothelial cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116165PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277463PMC
November 2015

Ramipril protects the endothelium from high glucose-induced dysfunction through CaMKKβ/AMPK and heme oxygenase-1 activation.

J Pharmacol Exp Ther 2014 Jul 16;350(1):5-13. Epub 2014 Apr 16.

Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)

This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKβ (Ca(2+)/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKβ/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKβ or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-β, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.
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http://dx.doi.org/10.1124/jpet.114.212928DOI Listing
July 2014

Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy.

Cancer Immunol Immunother 2013 Jun 21;62(6):1123-30. Epub 2013 Apr 21.

Department of Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Beijing 100142, China.

Purpose: Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers.

Experimental Design: This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured.

Results: Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis.

Conclusions: This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.
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http://dx.doi.org/10.1007/s00262-013-1424-8DOI Listing
June 2013

Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients.

Clin Transl Oncol 2013 Apr 10;15(4):331-4. Epub 2012 Nov 10.

Department of Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, China.

Aim: This study was designed to explore the genetic polymorphism of IL-10 (-1082A/G, -592A/C, -819T/C), TNF-α (-308G/A) with susceptibility to docetaxel-induced liver injury (DILI) in Chinese breast cancer patients.

Methods: The targeted genetic polymorphisms of IL10-1082G/A, IL10-592A/C, IL10-819T/C, TNF-308G/A from 40 patients with DILI were assayed by matrix-assisted laser desorption/ionization-time of flight of Sequenom.

Results: AA genotype of IL10-592 and TT of IL10-819 significantly increased incidence of DILI (P = 0.005, OR = 3.137). No differences of TNF gene polymorphism between the two groups were seen.

Conclusion: The genetic polymorphism of the IL10-592A/C AA genotype and IL10-819T/C TT genotype was predominantly conferred to the incidence of docetaxel-induced liver injury.
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http://dx.doi.org/10.1007/s12094-012-0936-6DOI Listing
April 2013

Clinical safety of induced CTL infusion through recombinant adeno-associated virus-transfected dendritic cell vaccination in Chinese cancer patients.

Clin Transl Oncol 2012 Sep 19;14(9):675-81. Epub 2012 Jul 19.

Department of Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, China), Peking University School of Oncology/Beijing Cancer Hospital and Institute, 52 Fucheng Rd, Beijing, 100142, China.

Aim: The aim of the study is to explore the safety of cytotoxic T lymphocytes (CTLs) infusion by transfected dendritic cells (DCs) with recombinant adeno-associated virus vector (rAAV) carrying CEA cDNA among advanced cancer patients.

Patients And Methods: A total of 27 cancer patients with tumor tissue expression positivity and/or sera-elevated level of CEA were subsequently divided into cohort A and B resulted from the ex vivo expansion number of CTLs generated from co-culture of specific transfected DCs with autologous T lymphocytes. Based on the variations of infused number of specific CTL derived from different yields of individualized patients who had experienced various anti-cancer treatments, we compared the patients of low number of CTL cells (2-8 × 10(8) infused, cohort A, 6 cases) with those of higher number (above 8 × 10(8) infused, cohort B, 21 cases) to testify the possible adverse reactions caused by amount of infused CTLs. This study resembled a phase I study aiming for setting up clinical trial of adoptive cellular therapy that conceptually comes from conventional cytotoxic drugs.

Results: The results showed that one case from the each cohort had experienced moderate fever, and four cases with fatigue were seen in cohort B. The symptoms were transient without serious adverse events. For the consideration of clinical response 2 partial remission (8.0 %, 2/25), 1 minor remission, and 9 stable disease (40 %, 10/25) were observed in 25 patients eligible for evaluation. Sera levels of CEA assay were lowered in six patients. During a median follow-up of 8.1 months, we could not observe severe or chronic adverse reactions related to rAAV-DC infusions. Meanwhile, the variation of number of CTLs infused in this setting did not alter the status of peripheral lymphocyte population.

Conclusions: These preliminary data suggest that the rAAV-DC immunotherapy is well-tolerated and showed no severe adverse reactions in cancer patients.
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http://dx.doi.org/10.1007/s12094-012-0854-7DOI Listing
September 2012

Non-genetic risk factors and predicting efficacy for docetaxel--drug-induced liver injury among metastatic breast cancer patients.

J Gastroenterol Hepatol 2012 Aug;27(8):1348-52

Department of Medical Oncology, Beijing Cancer Hospital, Peking University School of Oncology, Beijing, China.

Background And Aim: Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel-drug-induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear.

Methods: We conducted a retrospective cohort study to identify non-genetic risk factors for docetaxel-DILI among 647 metastasis breast cancer patients treated with docetaxel-containing regimens.

Results: Sixty-seven (10.36%) patients were diagnosed as docetaxel-DILI. By logistic regression analysis, premenopausal status (odds ratio [OR][95% confidence interval {CI}] = 2.24 [1.30-3.87]), past hepatitis B virus (HBV) infections (OR [95% CI] = 4.23 [1.57-11.42]), liver metastasis (OR [95% CI] = 3.70 [2.16-6.34]). The predominant occurrence of DILI was seen in groups with docetaxel combination regimens. (OR [95% CI] = 2.66 [1.59-4.55]). The potential increasing occurrence of docetaxel-DILI was associated with multiple risk factors in an exposure-response manner (P < 0.001), and patients with more than three risk factors would be exposed to a 36.61-fold risk of DILI (95% CI = 10.18-131.62). Further analysis by the risk score and area under the receiver-operator characteristic curve (AUC) showed that those four factors contributed to an AUC of 0.7536 (95% CI = 0.70-0.81), with a predictive sensitivity of 74.63% and specificity of 65.17%.

Conclusions: Docetaxel-DILI with a relatively higher incidence should be addressed among metastatic breast cancer patients. Four predominant risk factors, including premenopausal status, past HBV infection, liver metastasis, and docetaxel combination regimens, were potential predicators for DILI.
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http://dx.doi.org/10.1111/j.1440-1746.2012.07131.xDOI Listing
August 2012